Synthesis and in vitro study of 17β-[N-ureylene-N,N′-disubstituted]-4-methyl-4-aza-5α-androstan-3-ones as selective inhibitors of type I 5α-reductase Original Research Article

A series of 17β-(N-ureylene-N,N′-disubstituted)-4-azasteroids as inhibitors of human type I 5α-reductase (5α-Rc) were prepared from 17β-N-alkyl-4-methyl-4-aza-5α-androstan-3-ones and various isocyanates. For the measurement of 5α-Re activity, 293 cells transfected with human type I 5α-Re, cDNA were used. Azasteroids with an N-cyclopropyl ring exhibited potent inhibitory activity against type I 5α-Re. As the chain length increased, from the N′-ethyl to the N′-butyl chain, activity of compounds also increased and azasteroids with the N′-butyl chain showed strong inhibitory activity (IC50 = 5.3 nM). Branching of alkyl chains decreased the potency of compounds. Introduction of the 1,2-double bond significantly reduced the activity of azasteroids. Replacement of the N′-alkyl chain with the phenyl moiety gave the most active compound of this series (IC50 = 1.3 nM). Other variations such as the replacement of a N-cyclopropyl ring with the N-methyl or the N-butyl chain decreased the activity of compounds (compounds were less active compared with above). The IC50 values of N-methyl-N′-cyclohexyl- and N-butyl-N′-phenyl-ureylenes were 31.5 and 11.5 nM, respectively. In general, all azasteroids were poor inhibitors of Type II 5α-Re.